Research Initiative Treatment Action (RITA!); Vol 5, No. 5 December 1999
Tim Horn
If it ain't complicated it don't matter whether it works or not because if it ain't complicated up enough it ain't right.
–William Faulkner
Scientific research is so technologically advanced that it can answer some of the most baffling and complicated medical questions with relative ease. So why does it seem to take forever for researchers to provide simple explanations for the most basic dilemmas facing doctors and patients? A perfect example is HIV-related lipodystrophy, a rapidly emerging complication of HIV disease is characterized by body-shape changes and increases in lipid and cholesterol levels.
Despite a few years of intensive research underfoot, the cause of lipodystrophy is still unknown. Complicating matters more are recent reports suggesting that nucleoside analogs—particularly stavudine (Zerit)—may be a likely culprit behind the body's inability to control the amount of fat in the blood and tissues.
It seems as if things are only going to get more complicated before they get easier.
Approximately three years ago, reports began to surface that people on highly active antiretroviral therapy (HAART) were seeing their weight—and waist size—increase above and beyond what would be considered a healthy response to these powerful new therapies. Along with fat mass accumulation around the waist, some HIV-infected people began seeing the fat in their face and limbs disappear, causing veins to protrude and the outlines of muscle and bone to become glaringly visible. Other reports included narrowing thighs, loss of butt shape and size, the accumulation of fat between the shoulder blades and breast enlargement in women. Even more alarming were increased levels of lipids and cholesterol seen in patients' blood, putting some HIV-infected people on an apparent crash-collision course with heart attack, stroke, and possibly death.
Originally, lipodystrophy was thought to be a direct consequence of taking protease inhibitors. Although lipodystrophy's early nickname was "Crix belly" (after Crixivan), researchers correctly noted that it was being seen in patients taking any of the approved protease inhibitors, giving way to the more polite name "protease paunch."
Here is where things started to get messy.
Just in time for the 12th World AIDS Conference two summers ago in Geneva, researchers determined to uncover the cause of lipodystrophy were drawn into two distinct camps. One group, with Andrew Carr, MD, of St. Vincent's Hospital in Sydney taking the lead, was strong in its suggestions that protease inhibitors were the most likely culprits. As evidence, Carr and his colleagues found that protease inhibitors impair the function of two proteins in the body—LRP and CRABP—responsible for mopping up excess fats in the blood and keeping fat where it should be in the tissues. These data were more or less confirmed by a study conducted by a team of researchers at Glaxo Wellcome. Eureka? Well, that all depends on whom you ask.
Challenging Carr's hypothesis was a second group of physicians and researchers, with Donald Kotler, MD, of St. Luke's-Roosevelt Hospital Center in New York clearly at the helm. Kotler has been quick to point out that some HIV-infected patients with lipodystrophy are not taking protease inhibitors, and that a similar problem exists in HIV-uninfected patients, particularly those being treated for other chronic diseases. As an alternative hypothesis, Kotler suggested that lipodystrophy may not be a direct side effect of antiviral drug therapy but, instead, a negative repercussion of sharp viral load decreases and immune system recovery associated with HAART.
At the 1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, held in San Diego this past summer, multiple lines of evidence converged to suggest that HAART is definitely to blame. Both Kotler and Carr seem ready to accept that, while protease inhibitors may not be the only culprits, lipodystrophy is definitely a direct side effect of drug therapy.
Challenging Carr's original hypothesis are data from his own lab, along with those of a study conducted by researchers at Agouron Pharmaceuticals. According to Carr's presentation, approximately one-third of patients taking a treatment regimen that did not contain a protease inhibitor had signs and symptoms of lipodystrophy. As for the original CRABP-1 hypothesis, the Agouron research team demonstrated that protease inhibitors and CRABP-1 do not match up nearly as well as was previously suggested by Carr and the Glaxo Wellcome group, throwing a lot more questions than answers into the mix.
Kotler, on the other hand, has come to appreciate some of the large cohort studies currently under way. These studies have been looking at the association between antiviral therapy—consisting of protease inhibitor-, and non-protease inhibitor-based regimens—and the incidence of lipodystrophy. While there seems to be a clear association, Kotler points to data showing that patients who have been on therapy longest appear to be experiencing the worst symptoms of lipodystrophy. In other words, it is not necessarily the drugs, but the length of time patients have been taking them.
Causing many of those in attendance at the San Diego meeting to raise their eyebrows were a series of unexpected reports linking nucleoside analogs to lipodystrophy. Kees Brinkman, MD, of The Netherlands threw the first curveball upon launching into an exhaustive overview of the negative effects of nucleoside analogs on cellular mitochondria. Mitochondria are found in most human cells and are needed to produce energy for cells to function properly. According to Brinkman, mitochondrial damage helps explain many of the side effects associated with nucleoside analog therapy, including muscle loss (myopathy), peripheral neuropathy, pancreatitis and decreased white blood cell counts (cytopenia). Given that fat cells (adipocytes)—along with other cells involved in the proper metabolism of fats—contain mitochondria, Brinkman cautiously suggested that lipodystrophy might be yet another negative consequence of nucleoside analog therapy.
Following on the heels of Brinkman's report were the preliminary results of several small cohort studies linking nucleoside analog therapy, particularly stavudine, to lipodystrophy. Many of the studies presented—conducted in the United States, Europe, and Australia—focused on patients who were experiencing lipodystrophy while only taking two nucleoside analogs. All nucleoside analogs—which include zidovudine, didanosine (Videx), zalcitabine (Hivid), stavudine, lamivudine (Epivir) and abacavir (Ziagen)—were associated with some degree of body-shape changes. Focusing on stavudine, the rate appeared highest; patients receiving stavudine were two to 3 times more likely to have lipodystrophy than patients receiving nucleoside analog regimens that did not include stavudine. Moreover, when some patients switched their stavudine for another nucleoside analog, lipodystrophy improved within six months.
Do these results prove that stavudine is to blame? Not at all. For starters, not all studies focusing on the possible effects of nucleoside analogs found stavudine to be any worse than other drugs in the same group. Second, the results discussed above are based on "association," not "causation." In other words, no studies have yet demonstrated that stavudine causes lipodystrophy, only that some patients taking stavudine were more likely to experience body-shape changes than patients taking nucleoside analogs. With respect to these associations, it is important to note that not all patients taking stavudine in these studies experienced lipodystrophy.
Kotler remains interested, not so much in which nucleoside analog is being used, but rather on the length of time patients have been receiving drug therapy. Kotler notes that many patients who had been taking zidovudine for several years switched to stavudine once it became available in 1994. This distinction is important, as it suggests that stavudine is taking heat for damage that may have already been done.
As for the whole mitochondria hypothesis, Kotler has emphasized that it is too early to go pointing fingers. Perhaps Kotler's Medscape commentary on the San Diego workshop—published at www.medscape.com—sums things up best: "Unfortunately, it appeared that many people at the [San Diego] meeting came away with the impression that the link between mitochondrial toxicity and lipodystrophy was strong. In fact, the hypothesis has no direct proof, much like the [protease inhibitor] LRP/CRABP hypothesis, and should be seen for what it is: a specific construct whose validity can be tested in prospective studies. At present, the mitochondrial hypothesis should not be a consideration in treatment decision-making."
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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